Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Specificities and genomic distribution of somatic mammalian histone H1 subtypes☆
Introduction
For many years, most work on chromatin structure and function has been focused on the nucleosome core particle, composed of the core histones H2A, H2B, H3 and H4, and less attention has been paid to the linker histone H1, regarding its structure, function, post-translational modifications (PTMs), etc. Since the linker histone H1 was discovered in calf thymus as a lysine-rich family of histone proteins that differed in sequence composition [1], the study of these subtypes has remained challenging because of their high heterogeneity, which makes it difficult to obtain specific antibodies for all members of this family.
Compared with core histones, which are highly conserved in evolution, the linker histone H1 family is more divergent [2] and in several organisms many subtypes or variants are known to exist due to gene duplication events during evolution, from one variant in simple eukaryotes to eleven variants in humans or mice. The diversity of histones and the identification of an increasing number of variants have led to confusion in naming. Over the years, many attempts have been made to unify nomenclature (Table 1). Recently, in 2012, a unified phylogeny-based nomenclature was proposed for histone variants [3].
In humans and mice, the H1 family comprises eleven variants or subtypes, products of different paralog genes (Table 1). They can be classified according to various criteria: expression, cell cycle dependence, and gene location in the genome (see [4], [5], [6] for recent reviews). Specifically, seven human H1 variants are somatic subtypes (H1.1 to H1.5, H1.0 and H1X), while others are restricted to germ cells, with three testis-specific variants (H1t, H1T2 and HILS1) and one oocyte-specific variant (H1oo). For an extended review of germline-specific H1 variants in different species, see [7]. Among the somatic histone H1 variants, H1.1 to H1.5 are expressed in a replication-dependent manner through the cell cycle, whereas H1.0 and H1X are replication-independent. H1.2 to H1.5 and H1X are ubiquitously expressed, H1.1 is restricted to certain tissues and cell types (liver, kidney, lung, lymphocytes from thymus and spleen, neurons and germ cells), and H1.0 accumulates in terminally differentiated cells. Regarding gene location, H1.1 to H1.5-encoding genes are clustered in a region of chromosome 6, together with the core histone genes, whereas H1X and H1.0 are located on chromosome 3 and 22, respectively.
Genes located in large clusters on chromosome 6 (6p21–p22) are encoded by individual intronless genes, with short 5′ and 3′ ends. Transcripts lack polyA tails but contain a 3′ stem-loop sequence that allows for rapid translation during DNA replication. On the other hand, isolated genes such as H1.0 and H1X are also intronless, but their mRNA is polyadenylated. It is interesting to note that, although clustered genes share the same chromosome location and gene structure, they are not expressed equally, H1.1 and H1t ((TS) H1.6) showing tissue specificity and the expression of other subtypes fluctuating differently through the cell cycle [8]. Thus, it seems to be that transcription of different H1 variants is tightly regulated in order to achieve proper expression of each variant in different tissues or cells, but also during the cell cycle and differentiation. However, the exact molecular mechanisms by which this happens have yet to be identified. Little is known about histone H1 transcriptional regulation, but it is reported that specific sequences in their promoters modulate binding of transcription factors and chromatin proteins [9], [10], [11], [12].
Section snippets
Histone H1 variants: more than a redundant family of structural chromatin proteins
Due to its role in the formation of higher-order chromatin structures, H1 has been classically seen as a structural component related to chromatin compaction and inaccessibility to transcription factors, RNA polymerase, and chromatin remodeling enzymes [13], [14]. Many studies support this view, as the presence of H1 in promoter regions impairs transcription of the associated gene [15], [16], [17]. However, in recent years, the view that H1 plays a more dynamic and gene-specific role in
H1 variant sequence conservation
H1 variants are paralog genes, as they originate from gene duplication events. On the other hand, the corresponding variants within two species are orthologs, because they share a common ancestor before the event of speciation. H1 ortholog genes are much more conserved than paralog genes; this means that the primary sequence of a given H1 variant is more conserved across species than within variants from the same species. This evolutionary effort to conserve the sequence of a given H1 subtype
Genomic distribution of somatic histone H1 variants
To fully understand the biology of histone H1 and whether its variants locate distinctly, which might reflect specific functions, several groups have sought to explore the genomic distribution of H1 in vivo. However, due to the current lack of specific chromatin immunoprecipitation (ChIP)-grade antibodies for most of the H1 variants, the precise mapping of H1 variants in the genome has been challenging.
Concluding remarks
Although histone H1 variants show partial redundancy, the most recent research highlights that they also have specific functions in certain cellular processes and they present differences regarding regulation of gene expression and/or chromatin compaction, which can be explained by differential structural properties, interaction with specific partners due, in part, to differential post-translational modifications, or a heterogeneous genomic distribution. Based on the many studies described
Transparency document
Acknowledgements
We thank members of the lab for their feedback on the manuscript. This work was supported by the Spanish Ministry of Science and Innovation (MICINN) and the European Regional Development Fund (grant BFU2014-52237).
References (134)
- et al.
A structural comparison of different lysine-rich histones of calf thymus
J. Biol. Chem.
(1966) - et al.
Histone H1 and its isoforms: contribution to chromatin structure and function
Gene
(2009) - et al.
The transcriptional regulation of Xenopus 5 s RNA genes in chromatin: the roles of active stable transcription complexes and histone H1
Cell
(1984) - et al.
Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation
Cell
(2005) - et al.
The histone H1 complements of dividing and nondividing cells of the mouse
J. Biol. Chem.
(1983) - et al.
Changes in the proportions of histone H1 subtypes in brain cortical neurons
FEBS Lett.
(1987) - et al.
Histone H1 variants are differentially expressed and incorporated into chromatin during differentiation and reprogramming to pluripotency
J. Biol. Chem.
(2011) - et al.
Promyelocytic leukemia zinc finger and histone H1.5 differentially stain low- and high-grade pulmonary neuroendocrine tumors: a pilot immunohistochemical study
Hum. Pathol.
(2013) - et al.
N- and C-terminal domains determine differential nucleosomal binding geometry and affinity of linker histone isotypes H1(0) and H1c
J. Biol. Chem.
(2012) - et al.
H1 family histones in the nucleus. Control of binding and localization by the C-terminal domain
J. Biol. Chem.
(2005)
Effects of H1 histone variant overexpression on chromatin structure
J. Biol. Chem.
Linker histone subtypes differ in their effect on nucleosomal spacing in vivo
J. Mol. Biol.
Mass spectrometric mapping of linker histone H1 variants reveals multiple acetylations, methylations, and phosphorylation as well as differences between cell culture and tissue
Mol. Cell. Proteomics
Proteomic characterization of the nucleolar linker histone h1 interaction network
J. Mol. Biol.
Isolation and characterization of a novel H1.2 complex that acts as a repressor of p53-mediated transcription
J. Biol. Chem.
HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding
J. Biol. Chem.
Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin
Mol. Cell
Histone H1 variant, H1R is involved in DNA damage response
DNA Repair (Amst)
Reductions in linker histone levels are tolerated in developing spermatocytes but cause changes in specific gene expression
J. Biol. Chem.
Histone H1 variants play individual roles in transcription regulation in the DT40 chicken B cell line
Biochem. Biophys. Res. Commun.
Global gene expression analysis reveals specific and redundant roles for H1 variants, H1c and H1(0), in gene expression regulation
Gene
Genome distribution of replication-independent histone H1 variants shows H1.0 associated with nucleolar domains and H1X associated with RNA polymerase II-enriched regions
J. Biol. Chem.
Linker histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation
Cell Rep.
PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway
Mol. Cell
HMG-D and histone H1 interplay during chromatin assembly and early embryogenesis
J. Biol. Chem.
HP1 is involved in regulating the global impact of DNA methylation on alternative splicing
Cell Rep.
Proteomic profiling of the human T-cell nucleolus
Mol. Immunol.
H1.X with different properties from other linker histones is required for mitotic progression
FEBS Lett.
Linker histone subtypes are not generalized gene repressors
Biochim. Biophys. Acta
Origin of H1 linker histones
FASEB J.
A unified phylogeny-based nomenclature for histone variants
Epigenetics Chromatin
H1 Histones: Current Perspectives and Challenges
Nucleic Acids Res.
The histone H1 family: specific members, specific functions?
Biol. Chem.
Germline-specific h1 variants: the “sexy” linker histones
Chromosoma
H1 subtype expression during cell proliferation and growth arrest
Cell Cycle
An H1 histone gene-specific 5′ element and evolution of H1 and H5 genes
Nucleic Acids Res.
Organization and expression of H1 histone and H1 replacement histone genes
J. Cell. Biochem.
Role of a distal promoter element in the S-phase control of the human H1.2 histone gene transcription
Eur. J. Biochem./FEBS
Multilayered chromatin analysis reveals E2f, Smad and Zfx as transcriptional regulators of histones
Nat. Struct. Mol. Biol.
Influence of linker histone H1 on chromatin remodeling
Biochem. Cell Biol.
Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-beta-catenin signaling pathway
Mol. Cell. Biol.
CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis
Nat. Cell Biol.
The rhox homeobox gene cluster is imprinted and selectively targeted for regulation by histone h1 and DNA methylation
Mol. Cell. Biol.
Individual somatic H1 subtypes are dispensable for mouse development even in mice lacking the H1(0) replacement subtype
Mol. Cell. Biol.
H1 linker histones are essential for mouse development and affect nucleosome spacing in vivo
Mol. Cell. Biol.
Birth-and-death evolution with strong purifying selection in the histone H1 multigene family and the origin of orphon H1 genes
Mol. Biol. Evol.
Evolution of the vertebrate H1 histone class: evidence for the functional differentiation of the subtypes
Mol. Biol. Evol.
Varied expression patterns of human H1 histone genes in different cell lines
DNA Cell Biol.
A compendium of the histone H1 family of somatic subtypes: an elusive cast of characters and their characteristics
Biochem. Cell Biol.
Alteration in proportions of histone H1 variants during the differentiation of murine erythroleukaemic cells
Biochem. J.
Cited by (0)
- ☆
This article is part of a Special Issue entitled: Histone H1, edited by Dr. Albert Jordan.
- 1
Present address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.